Variations in dietary sodium intake initiate integrated adjustments in neural and hormonal systems regulating sodium excretion by the kidneys in order to maintain overall sodium balance. These adjustments remain incompletely understood despite intensive study. In addition, a complex relationship exists between sodium balance and blood pressure such that high dietary sodium intake provokes hypertension in susceptible individuals. Studies from our laboratory have identified a previously unrecognized hormonal system which participates in the maintenance of sodium balance on a high sodium intake. This system involves the synthesis of the prohormone proopiomelanocortin (POMC) in the pituitary, and its processing into the secreted natriuretic peptide gamma-melanocyte stimulating hormone (gamma-MSH). This system is activated by a high sodium diet in rats, mice, and humans, and fails to respond to sodium loading in rodents with genetic forms of hypertension. We shall characterize the hypertension seen with dietary sodium loading in mice with gamma-MSH deficiency due to targeted disruption of the proconvertase 2 gene, necessary for processing of POMC into gamma-MSH, and establish that the hypertension is corrected by infusion of gamma-MSH. We shall also evaluate the consequences of inhibition of gamma-MSH release from the pituitary by dopaminergic stimulation in rats fed a high sodium diet, and test the effects of sodium loading in mice lacking melanocortin receptors with which gamma-MSH interacts. In addition, we shall characterize the nature and location of renal melanocortin receptors, and determine if their expression is altered by a high sodium diet. We shall determine if gamma-MSH acts centrally to inhibit sympathetic nervous outflow and lower blood pressure in hypertensive PC2 -/- mice on the high sodium diet. Finally, we shall examine the effects of high vs low sodium diets on blood pressure and plasma gamma-MSH concentration in normal subjects and patients with mild essential hypertension studied in a General Clinical Research Center to determine if this system functions in humans in a manner parallel to that in rodents and evaluate if individuals with salt-sensitive hypertension demonstrate blunted activation of the system. These studies should extend our understanding of the integrated regulation of sodium balance when challenged with a high sodium intake, and the relationship between sodium intake and the development of hypertension, by providing mechanistic insight into a novel and previously unrecognized system activated by high dietary sodium intake.